The present invention relates to certain novel substituted piperidine derivatives, to processes for their preparation, to pharmaceutical formulations containing them and to their use in medical therapy, particularly in the treatment of psychotic disorders.
U.S. Pat. No. 2,739,968 describes substituted piperidine derivatives having antihistaminic, antispasmodic, antiacetylcholine and analgesic activity. U.S. Pat. Nos. 4,666,905 and 4,540,780 describe diphenylmethylene derivatives which are useful as antiemetic, antihistamine, pulmonary antispasmodic agents.
Effective antipsychotic (neuroleptic) agents include tricyclic phenothiazines, thioxanthenes and dibenzepines as well as benzamides and butyrophenones. These compounds block dopamine D2 receptors and inactivate dopamine transmission. As a result of this, these compounds induce characteristic neurological side effects in man such as extrapyramidal side effects e.g. dystonia and dyskinesia (R. J. Baldessarini, 1996, Goodman and Gilman""s The Pharmacological Basis of Therapeutics 9th ed., eds J. G. Hardman et. al.). In animal tests such side effects manifest themselves as catalepsy. It would be advantageous therefore to provide a series of antipsychotic agents which do not have these debilitating side effects.
The present invention provides certain substituted piperidine derivatives which have potent antipsychotic activity but exhibit minimal or no cataleptic effects, and thus would not induce extrapyramidal side effects in the therapeutic dose range.
Thus, according to one aspect, the present invention provides the compounds of formula (I) 
wherein
R1 is benzothienyl, benzofuranyl, naphthyl (where the benzothienyl, benzofuranyl or naphthyl moiety may be optionally substituted by one or more substituents selected from halogen, C1-6alkyl, C3-6cycloalkyl, C1-6alkoxy and C2-6alkenyl), substituted-thienyl or substituted-furanyl (where the thienyl or furanyl moiety is substituted by one or more substituents selected from halogen, C1-6alkyl, C3-6cycloalkyl, C1-6alkoxy and C2-6alkenyl);
R2 is substituted-phenyl or substituted-thienyl (where the phenyl or thienyl moiety is substituted by one or more substituents selected from C1-6alkyl and halogen);
R3 is xe2x80x94(CH2)mXCONR4R5 or xe2x80x94(CH2)mNR6COR7 wherein R4 is hydrogen or C1-6alkyl and R5 is hydrogen, C1-6ealkyl, C3-6cycloalkyl, C6-12aryl, C6-12arylC1-6alkyl or a C3-9heterocyclic group (where the alkyl, aryl or heterocyclic moiety may be optionally substituted by one or more substituents selected from halogen, C1-6alkyl, C3-6cycloalkyl, C1-6alkoxy and C2-6alkenyl), or R4 and R5 together with the nitrogen atom to which they are attached form a 4-10-membered heterocyclic group (optionally substituted by one or more substituents selected from halogen, C1-6alkyl, C3-6cycloalkyl, C1-6alkoxy and C2-6alkenyl), R6 is hydrogen or C1-6alkyl, R7 is C3-6cycloalkyl, C3-6cycloalkyl-C1-6alkyl, C6-12aryl, C6-12arylC1-6alkyl or a C3-9heterocyclic group (where the alkyl, aryl heterocyclic moiety may be optionally substituted by one or more substituents selected from halogen, C1-6alkyl, C3-6cycloalkyl, C1-6alkoxy and C2-6alkenyl), X is a bond, C6-12aryl or a 5- or 6-membered heteroaryl (where the aryl or heteroaryl moiety is optionally substituted by one or more substituents selected from halogen, C1-6alkyl, C3-6cycloalkyl, C1-6alkoxy and C2-6alkenyl);
wherein m is an integer 1, 2, 3 or 4;
or a pharmaceutically acceptable salt or solvate thereof.
As used herein the term alkyl means a straight or branched chain alkyl group. Such alkyl groups include methyl, ethyl, i-propyl, n-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, isohexyl and neohexyl. Such alkyl groups are preferably C1-4alkyl. Reference to cycloalkyl includes cyclopropyl and cyclopentyl.
References to alkenyl groups include groups which may be in the E- or Z-form or a mixture thereof and which when they contain at least three carbon atoms, may be branched. Such alkenyl groups are preferably C2-4alkenyl Examples of particular alkenyl groups include vinyl, allyl, isopropenyl, butenyl, isobutenyl, pentenyl, isopentenyl, hexenyl, isohexenyl and neohexenyl.
The term halogen includes chloro, bromo, fluoro and iodo.
As used herein the term aryl as a group or part of a group means C6-12aryl aromatic groups and includes one or two C6 aromatic rings. Examples of such groups include phenyl, naphthyl, and biphenyl, in particular phenyl.
As used herein the term C3-9heterocyclic group means aromatic, saturated and partially saturated C3-9heterocyclic groups. It includes one or two C3-5 aromatic, saturated or partially saturated rings containing one or more (for example, one to three) heteroatoms selected from oxygen, sulphur, and nitrogen. Examples of such aromatic groups include thienyl, pyridyl, pyrryl, thiazolyl, furanyl, quinolyl and isoquinolyl. Examples of unsaturated groups include piperidinyl pyrrolidinyl and azetidinyl.
The term 5- or 6-membered heteroaryl means a 5- or 6-membered aromatic ring containing one or more (for example, one to three, preferably one) heteroatoms selected from oxygen, sulphur, and nitrogen. For example, thienyl, pyridyl, pyrryl, thiazolyl and furanyl.
The term 4-10 membered heterocyclic ring means an aromatic, saturated or partially saturated 4, 5, 6, 7, 8, 9 or 10 membered ring containing one or more (for example, one to three, preferably one) heteroatoms selected from oxygen, sulphur, and nitrogen. Examples of such aromatic groups include thienyl, pyridyl, pyrryl, thiazolyl, furanyl, quinolyl and isoquinolyl. Examples of unsaturated groups include piperidinyl, pyrrolidinyl and azetidinyl.
The benzothienyl, benzofuranyl, naphthyl, substituted-thienyl and substituted-furanyl moieties include 2- and 3-benzothienyl, 2- and 3-benzofuranyl, 2- and 3-naphthyl, substituted-2-thienyl, substituted-3-thienyl, substituted-2-furanyl and substituted-3-furanyl groups. The benzothienyl, benzofuranyl, naphthyl, thienyl and furanyl ring substituent(s) may be in any one of the available positions. Specific examples of ring substituents include fluoro, chloro and methoxy.
The present invention further includes the compounds of formula (I) or a pharmaceutically acceptable salt or solvate thereof wherein:
(i) R1 is benzothienyl or substituted-thienyl (where the thienyl moiety substituent is C1-6alkyl, for example, methyl and ethyl);
(ii) R2 is a substituted-phenyl (where the phenyl moiety substituent is a halogen, for example, fluoro);
(iii) R3 is xe2x80x94(CH2)mXCONR4R5 wherein R4 and R5 together with the nitrogen atom to which they are attached form a 4, 5 or 6-membered heterocyclic group, for example, piperidine, pyrrolidine and azetidine, X is a bond or a C6aryl, for example, phenyl, and m is an integer 1, 2, 3 or 4, in particular 1 or 4;
(iv) R3 is xe2x80x94(CH2)mNR6COR7 wherein R6 is hydrogen, R7 is C3-6cycloalkyl, for example cyclopropyl, C3-6cycloalkylC1-6alkyl, for example, cyclopentylmethyl, C6aryl, optionally substituted by one or more C1-6alkyl groups, for example phenyl optionally substituted by methyl, m is an integer 1, 2, 3 or 4, in particular 2, 3 or 4;
(v) R1, R2 and R3 are as defined in points (i) to (iv) above;
Further examples of compounds of formula (I) above include the compounds described in Examples 2 and 3.
Preferred compounds according to the present invention include compounds of formula (I) wherein X is C6-12aryl or a 5- or 6-membered heteroaryl (where the aryl or heteroaryl moiety is optionally substituted by one or more substituents selected from halogen, C1-6alkyl, C3-6cycloalkyl, C1-6alkoxy and C2-6alkenyl); or a pharmaceutically acceptable salt or solvate thereof
Particularly preferred compounds according to the invention are:
1-[4-[4-[(4-fluorophenyl)(4-methylthien-2-yl)methylene]piperidin-1-yl]-1-oxobutyl]-piperidine (1:1) ethanedicarboxylate;
1-[4-[4-[(4-fluorophenyl)(4-methylthien-2-yl)methylene]piperidin-1-yl]-1-oxobutyl]-pyrrolidine. dihydrochloride;
1-[4-[4-[(3-fluorophenyl)(4-methylthien-2-yl)methylene]piperidin-1-yl]-1-oxobutyl]-piperidine. hydrochloride;
1-[3-[4-[(4-fluorophenyl)(4-methylthien-2-yl)methylene]piperidin-1-ylmethyl]benzoyl]piperidine;
1-[3-[4-[(4-fluorophenyl)(4-methylthien-2-yl)methylene]piperidin-1-ylmethyl]benzoyl]pyrrolidine.hydrochloride;
1-[3-[4-[(4-fluorophenyl)(benzothien-2-yl)methylene]piperidin-1-ylmethyl]benzoyl]piperidine.maleate;
1-[3-[4-[(4-fluorophenyl)(benzothien-2-yl)methylene]piperidin-1-ylmethyl]benzoyl]pyrrolidine.maleate;
1-[3-[4-[(4-fluorophenyl)(4-ethylthien-2-yl)methylene]piperidin-1-ylmethyl]benzoyl]piperidine.fumarate;
1-[3-[4-[(4-fluorophenyl)(4-ethylthien-2-yl)methylene]piperidin-1-ylmethyl]benzoyl]pyrrolidine.bis hydrochloride;
4,4-dimethyl-1-[3-[4-[(4-fluorophenyl)(4-methylthien-2-yl)methylene]-piperidin-1-ylmethyl]benzoyl]azetidine.maleate;
and pharmaceutically acceptable salts and solvates thereof.
For therapeutic use, salts of the compounds of formula (I) are those wherein the counterion is pharmaceutically acceptable. However, salts of acids which are non-pharmaceutically acceptable may also find use, for example, in the preparation or purification of a pharmaceutically acceptable compound. All salts, whether pharmaceutically acceptable or not are included within the ambit of the present invention.
Examples of pharmaceutically acceptable acid addition salts include those derived from mineral acids such as hydrochloric, hydrobromic, hydroiodic, phosphoric, metaphosphoric, nitric and sulphuric acids, and organic acids, such as tartaric, acetic, trifluoroacetic, citric, malic, lactic, maleic, malonic, fumaric, benzoic, ascorbic, propionic, glycolic, gluconic, succinic and methanesulphonic and arylsulphonic, for example benzene or p-toluenesulphonic acids.
Preferred salts according to the invention include hydrochloric, maleic, succinic and fumaric acid addition salts.
Solvates according to the invention include hydrates.
In a further aspect of the invention there are provided the compounds of formula (I) and their pharmaceutically acceptable salts and solvates for use in therapy, more particularly in the treatment or prophylaxis of psychotic disorders such as schizophrenia, mania, hyperactivity, substance abuse, emesis and schizophreniaform disorders.
The present invention further includes a method for the treatment of an animal, for example, a mammal including a human, suffering from or liable to suffer from a psychotic disorder, including any of the aforementioned disorders, which comprises administering an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof.
In yet a further aspect, the present invention provides the use of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof in the manufacture of a medicament for the treatment or prophylaxis of any of the aforementioned disorders.
The amount of a compound of formula (I) or a pharmaceutically acceptable salt or solvate, also referred to herein as the active ingredient, which is required to achieve a therapeutic effect will, of course, vary with the particular compound, the route of administration, the age and condition of the recipient, and the particular disorder or disease being treated.
A suitable daily dose for any of the above mentioned disorders will be in the range of 0.001 to 25 mg per kilogram body weight of the recipient (e.g. a human) per day, preferably in the range of 0.1 to 10 mg per kilogram body weight per day and most preferably in the range 0.25 to 5 mg per kilogram body weight per day. The desired dose may be presented as one, two, three, four, five or more sub-doses administered at appropriate intervals throughout the day.
While it is possible for the active ingredient to be administered alone, it is preferable to present it as a pharmaceutical formulation. Accordingly, the present invention further provides a pharmaceutical formulation comprising a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, together with a pharmaceutically acceptable carrier thereof and optionally other therapeutic agents. The carrier must be xe2x80x9cacceptablexe2x80x9d in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipients thereof.
Formulations include those suitable for oral, rectal, nasal, topical (including transdermal, buccal and sublingual), vaginal or parenteral (including subcutaneous, intramuscular, intravenous, intradermal and intravitreal) administration. The formulations may be prepared by any methods well known in the art of pharmacy, for example, using methods such as those described in Gennaro et al., Remington""s Pharmaceutical Sciences (18th ed., Mack Publishing company, 1990, see especially Part 8: Pharmaceutical Preparations and their Manufacture). Such methods include the step of bringing into association the active ingredient with the carrier which constitutes one or more accessory ingredients. Such accessory ingredients include those conventional in the art, such as, fillers, binders, diluents, disintegrants, lubricants, colorants, flavoring agents and wetting agents.
Formulations suitable for oral administration may be presented as discrete units such as pills, tablets or capsules each containing a predetermined amount of active ingredient; as a powder or granules; as a solution or suspension. The active ingredient may also be presented as a bolus or paste, or may be contained within liposomes.
Formulations for rectal administration may be presented as a suppository or enema.
For parenteral administration, suitable formulations include aqueous and non-aqueous sterile injection. The formulations may be presented in unit-dose or multi-dose containers, for example, sealed vials and ampoules, and may be stored in a freeze dried (lyophilised) condition requiring only the addition of the sterile liquid carrier, for example, water prior to use.
Formulations suitable for administration by nasal inhalation include fine dusts or mists which may be generated by means of metered dose pressurised aerosols, nebulisers or insufflators.
The present invention further includes the following processes for the preparation of compounds of formula(I).
The compounds of formula (I) may be produced by various methods known in the art of organic chemistry chemistry in general. Starting materials are either known and readily available from chemical sources or may themselves be produced by conventional techniques. For example, the compounds may be synthesised using methods described in The Chemistry of Heterocyclic Compounds, vol 44 xe2x80x9cThiophene and its derivativesxe2x80x9d, parts 1-5, Ed S. Gronowitz J. Wiley and Sons, and A. R. Katritsky and C. W. Rees, Comprehensive Heterocyclic Chemistry, Part 4 Ed C. W. Bird and G. H. Cheesman, Pergamon Press.
For example, compounds of formula (I) may be prepared by methods analogous to those disclosed in U.S. Pat. No. 4,540,780.
In the following description the symbols R1, R2, R3, R4, R5, R6, R7, X and m have the meanings ascribed to them in formula (I) unless otherwise stated.
Compounds of formula (I) may be prepared by reacting a compound of formula (II) 
with a compound of formula R3-L wherein L is a suitable leaving group, such as halogen, for example, chloro, bromo or iodo or methanesulphonyl (mesyl) or toluenesulphonyl (tosyl). The reaction may conveniently be carried out in the presence of a solvent such as toluene or ethanol at a temperature in the range of 60-110xc2x0 C.
Typically, a compound of formula (II) is reacted with an agent such as 1-(3-halomethylbenzoyl)piperidine, 1-(3-halo-methylbenzoyl)pyrrolidine, (4-halo-1-oxobutyl)piperidine (where halo includes chloro, bromo or iodo) or the corresponding mesyl or tosyl derivatives such as (4-mesyloxy-1-oxo-butyl)piperidine, in toluene or ethanol in the presence of a acid scavenger such as triethylamine or potassium carbonate, conveniently at room temperature or at higher temperature up to reflux.
Alternatively, compounds of formula (I) may be prepared from an amine of formula (III) 
by acylation. For example, by reacting a compound of formula (III) with the appropriate acid chloride of formula R7COCl.
Amines of formula (III) wherein R6 is an alkyl group may be prepared by alkylation of the corresponding compound of formula (III) wherein R6 is hydrogen using methods known in the chemical literature, for example, with ethyl iodide or methylated by pyrolysis of the formic acid salt prior to acylation, or using reductive alkylation methods.
Where necessary or desired, following one of the above processes, any one or more of the following further steps in any order may be performed:
(i) converting a pharmaceutically acceptable salt or solvate of a compound of formula (I) into a compound of formula (I).
(ii) converting a pharmaceutically acceptable salt or solvate of a compound of formula (I) into another pharmaceutically acceptable salt or solvate of formula (I).
(iii) converting a compound of formula (I) into a pharmaceutically acceptable salt or solvate of a compound of formula (I)
Compounds of formula (II) may conveniently be prepared by dehydration of a compound of formula (IV) 
wherein R8 is hydrogen or a nitrogen protecting group, such as trityl. Dehydration is typically carried out using a mineral acid such as hydrochloric acid or by using phosphorus oxychloride. The reaction may be conveniently carried out using standard conditions for dehydration of an alcohol. For example, by use of phosphorus oxychloride in the presence of a suitable solvent such as pyridine at a temperature in the range of 80 to 120xc2x0 C.
Other methods well known to a skilled person or readily available from the chemical literature may be used for the dehydration, including sulphuric acid, 4-methylbenzenesulphonic acid, trifluoroacetic acid, methanesulphonic acid, trifluoromethanesulphonic acid, thionyl chloride, or by use of Martin sulphurane dehydrating agent, employing, where necessary the appropriate solvent.
Compounds of formula (IV) supra wherein R6 is a nitrogen protecting group, for example, trityl may, using methods well known to a skilled person or readily available from the chemical literature, be either simultaneous or sequential dehydrated and deprotected to form a compound of formula (II)
Compounds of formula (IV) may be prepared by treating compounds of formula (V) 
wherein R8 is hydrogen or a nitrogen protecting group, with an appropriate organometallic reagent, such as a Grignard, or a lithium reagent derived from R2-L in which L is an appropriate halogen, such as bromo or chloro, or a lithio reagent derived from an activated aryl hydrogen atom. For example, compounds of formula (IV) wherein R2 is a phenyl group substituted with a halo atom may conveniently be prepared by treating a compound of formula (V) with the appropriate halo substituted phenyl magnesium halide using standard reaction conditions.
Compounds of formula (IV) may also be prepared by treating compounds of formula (VI) 
wherein R8 is hydrogen or a nitrogen protecting group, with an appropriate organometallic reagent, such as a Grignard, or a lithium reagent derived from R1-L in which L is an appropriate halogen, such as bromo or chloro, or a lithio reagent derived from an activated aryl hydrogen atom. The reaction is typically carried out in the presence of an apolar aprotic solvent such as ether or tetrahydrofuran at a temperature in the range of xe2x88x9260 to 67xc2x0 C.
Compounds of formula (V) may be prepared by methods known in the chemical literature. For example, compounds wherein R1 is 4-chloro- or 2,3-dichloro-thienyl may be prepared, for example, as described in example 1 by chlorination of the appropriately substituted halobenzoylthiophene. These compounds are commercially available or are prepared using methods known in the art, for example, by Friedal-Crafts benzoylation of the thiophene or other groups represented by R1.
Compounds of formulae (V) and (VI) may, for example, be prepared by the addition of the appropriate Grignard reagent to ethyl N-methyl or N-trityl isnicotinate. The latter compounds are commercially available or may be prepared from commercially available compounds using methods known in the art.
Alternatively, compounds of formula (VI) wherein R8 is acyl or hydrogen and R2 is 4-fluoro-phenyl may be prepared by methods described in J. Med. Chem., 1970, 13, 1. Compounds of formula (V) wherein R8 is trityl may be prepared from compounds of formula (V) wherein R8 is hydrogen, for example by reaction with trityl bromide using the method described in example 4 infra. Compounds of formula R3-L supra may, for example, be prepared by reacting the appropriate carbonylchloride with a suitable amine using methods known to a skilled person.
Compounds of formula (III) supra may be prepared by reacting a compound of formula (II) with the appropriate haloalkyphthalimides, followed by treatment of the intermediate N-alkylphthalimide with hydrazine using methods known in the art.
In the alternative, compounds of formula (III) wherein m is 2 and R6 is hydrogen may be prepared, for example, by treating compounds of formula (II) with bromoacetonitrile in the presence of potassium carbonate and acetonitrile or DMF. This intermediate is subsequently reduced using reagents suitable for the reduction of nitriles to amines. Suitable reducing agents include hydrides such as lithium aluminium hydride.
Salts according to the present invention may be prepared by treating a compound of formula (I) with an appropriate base, for example an alkali metal, alkaline earth metal or ammonium hydroxide, or an appropriate organic or inorganic acid, such as hydrochloric, fumaric or maleic acid.
The present invention further includes all novel intermediates described herein and in particular compounds of formula (II).